Compounds

Abstract

Provided are novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of or prevention of diseases associated with or characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

1 - 20 . (canceled) 
     
     
         21 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of CN, C 1-3  alkyl, C 1-3  alkoxy, C 1-3 haloalkyl, and C 3  cycloalkyl; 
 R 2  is selected from the group consisting of H, halo, CN, C 1-3 alkyl and C 1-3  haloalkyl; 
 R 3  is selected from the group consisting of:
 a) an N-linked 4-6 membered heterocyclyl ring optionally substituted with one or two substituents independently selected from the group consisting of halo, hydroxyl, C 1-6 alkyl and C 1-6  alkoxyl,
 wherein:
 the C 1-6 alkyl group is optionally substituted with one or two substituents independently selected from the group consisting of: halo, hydroxyl, C 1-3 alkoxy and cyclopropyl, and 
 the C 1-6  alkoxyl group is optionally substituted with one or two substitutents independently selected from the group consisting of halo, hydroxyl and C 1-3  alkoxyl; and 
 when the N-linked 4-6 membered heterocyclyl ring contains a substitutable nitrogen atom, the N-linked 4-6 membered heterocyclyl ring optionally is substituted by a 4-6 membered heterocyclyl ring; 
 wherein: 
  the 4-6 membered heterocyclyl ring optionally is substituted with one, two or three substitutents independently selected from halo, hydroxyl, and C 1-3  alkoxyl, 
 
 provided that: 
 the 4-6 membered heterocyclyl ring is attached to said substitutable nitrogen atom of the N-linked 4-6 membered heterocyclyl ring; 
 
 b) NHR 8 ; and 
 c) OR 8 ; 
 
 R 4  and R 5  are independently selected from the group consisting of H, hydroxyl and halo; 
 R 6  is halo, hydroxyl or —(CH 2 ) n SO 2 C 1-3 alkyl;
 wherein:
 n is 0, 1, 2 or 3; 
 
 
 R 7  is selected from the group consisting of H, Cyclopropyl, C 1-3  alkyl, —CH 2 CH 2 — and CH 2 CH 2 CH 2 —;
 wherein:
 the C 1-3 alkyl optionally is substituted with one, two or three substitutents independently selected from the group consisting of halo, hydroxyl, and C 1-3  alkoxyl; 
 in the —CH 2 CH 2 CH 2 —, one terminal carbon joins with the carbon atom to which another terminal carbon atom is attached to form a ring; 
 
 
 R 8  is independently selected from the group consisting of a C 4-6  cycloalkyl and a 4-6 membered heterocyclyl that contains nitrogen or oxygen
 wherein:
 the C 4-6  cycloalkyl group optionally substituted with one, two or three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3  alkoxyl and C 1-3  alkyl; 
 the 4-6 membered heterocyclyl that contains nitrogen or oxygen optionally is substituted with one or more substitutents independently selected from the group consisting of halo, hydroxyl, C 1-3  alkoxyl and C 1-3  alkyl, 
 wherein:
 the C 1-3  alkyl group of the C 4-6  cycloalkyl group and the 4-6 membered heterocyclyl group, respectively, optionally is substituted with one two or three substituents independently selected from halo and hydroxyl; or 
 
 
 
 
       a pharmaceutically acceptable salt thereof. 
     
     
         22 . The compound of Formula (I) or pharmaceutically acceptable salt according to  claim 21 , wherein R 1  is selected from the group consisting of C 1-3  alkyl and C 1-3  alkoxyl. 
     
     
         23 . The compound of Formula (I) or pharmaceutically acceptable salt according to  claim 21 , wherein R 2  is selected from the group consisting of H, halo and C 1-3 alkyl. 
     
     
         24 . The compound of Formula (I) or pharmaceutically acceptable salt according to  claim 21 , wherein R 4  and R 5  are independently selected from the group consisting of H and fluoro. 
     
     
         25 . The compound of Formula (I) or pharmaceutically acceptable salt according to  claim 24 , wherein R 4  and R 5  are both H. 
     
     
         26 . The compound of Formula (I) or pharmaceutically acceptable salt according to  claim 21 , wherein:
 R 3  is an N-linked 4-6 membered heterocyclyl ring optionally substituted with one or two substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkyl and C 1-3  alkoxyl;
 wherein:
 the C 1-3  alkyl group optionally is substituted with one or two substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxy, and 
 the C 1-3  alkoxyl group is optionally substituted with one or two substitutents independently selected from halo, hydroxyl and C 1-3  alkoxyl. 
 
   
     
     
         27 . The compound of Formula (I) or pharmaceutically acceptable salt according to  claim 21 , wherein R 6  is fluoro or hydroxyl. 
     
     
         28 . The compound of Formula (I) or pharmaceutically acceptable salt according to  claim 21 , wherein R 7  is H. 
     
     
         29 . A compound which is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         30 . A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to  claim 21  and at least one pharmaceutically acceptable excipient(s). 
     
     
         31 . A method for treating a neurodegenerative disease, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt according to  claim 21 . 
     
     
         32 . The method for treating a neurodegenerative disease according to  claim 31 , wherein the neurodegenerative disease is Parkinson's disease. 
     
     
         33 . The method for treating a neurodegenerative disease according to  claim 32 , wherein the subject is a human. 
     
     
         34 . The method for treating a neurodegenerative disease according to  claim 33 , wherein the subject is a human expressing the G2019S mutation in the LRRK2 kinase.